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The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation

Author

Listed:
  • Christopher B. Nelson

    (University of Sydney)

  • Samuel Rogers

    (University of Sydney)

  • Kaushik Roychoudhury

    (Cincinnati Children’s Hospital Medical Center)

  • Yaw Sing Tan

    (Agency for Science, Technology and Research (A*STAR))

  • Caroline J. Atkinson

    (UNSW Medicine & Health, UNSW Sydney)

  • Alexander P. Sobinoff

    (University of Sydney)

  • Christopher G. Tomlinson

    (University of Sydney)

  • Anton Hsu

    (University of Sydney)

  • Robert Lu

    (University of Sydney)

  • Eloise Dray

    (University of Texas Health Science Center at San Antonio)

  • Michelle Haber

    (UNSW Medicine & Health, UNSW Sydney)

  • Jamie I. Fletcher

    (UNSW Medicine & Health, UNSW Sydney)

  • Anthony J. Cesare

    (University of Sydney)

  • Rashmi S. Hegde

    (Cincinnati Children’s Hospital Medical Center)

  • Hilda A. Pickett

    (University of Sydney)

Abstract

The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a phosphotyrosine signalling network governing PLK1 and mitosis.

Suggested Citation

  • Christopher B. Nelson & Samuel Rogers & Kaushik Roychoudhury & Yaw Sing Tan & Caroline J. Atkinson & Alexander P. Sobinoff & Christopher G. Tomlinson & Anton Hsu & Robert Lu & Eloise Dray & Michelle H, 2024. "The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45683-4
    DOI: 10.1038/s41467-024-45683-4
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    References listed on IDEAS

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    1. Fumiko Toyoshima-Morimoti & Eri Taniguchi & Nobuko Shinya & Akihiro Iwamatsu & Eisuke Nishida, 2001. "Erratum: Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase," Nature, Nature, vol. 410(6830), pages 847-847, April.
    2. Fumiko Toyoshima-Morimoto & Eri Taniguchi & Nobuko Shinya & Akihiro Iwamatsu & Eisuke Nishida, 2001. "Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase," Nature, Nature, vol. 410(6825), pages 215-220, March.
    3. Owen Addis Jones & Ankana Tiwari & Tomisin Olukoga & Alex Herbert & Kok-Lung Chan, 2019. "PLK1 facilitates chromosome biorientation by suppressing centromere disintegration driven by BLM-mediated unwinding and spindle pulling," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
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